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TRIP13 AAA-ATPase overexpression in chromosomal instability and breast cancer

TRIP13 AAA-ATPase 在染色体不稳定和乳腺癌中过度表达

基本信息

批准号：
9057001
负责人：
Song-Tao Liu
金额：
$ 30.61万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057001
关键词：
ATP Hydrolysis ATP phosphohydrolase Adaptor Signaling Protein Address Affect Agar Anaphase Aneuploid Cells Aneuploidy Animals Automobile Driving Biochemical Breast Cancer Cell Breast Epithelial Cells Cancer Cell Growth Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cells Characteristics Chromosomal Instability Chromosomal Stability Complex Cytogenetics Development Diagnosis Diploid Cells Disadvantaged Drug Targeting Engineering Enzymes Epigenetic Process Exhibits Genes Genetic Genome Genome Stability Growth Investigation Kinetochores Knowledge Long-Term Effects MCF10A cells MXD1 gene MXI1 gene Macromolecular Complexes Malignant Neoplasms Metaphase Mitosis Mitotic Mitotic Checkpoint Modeling Molecular Mutation Neoplastic Cell Transformation Non-Malignant Nude Mice Oncogene Activation Oncogenic Outcome Proteins Public Health Research Saccharomycetales Signal Transduction Solid Neoplasm TP53 gene Testing Tumor Suppressor Proteins Validation Work Xenograft procedure Yeasts base cancer cell cancer prevention cell transformation data mining fitness genetic signature innovation insight interest knock-down live cell imaging malignant breast neoplasm member mouse model neoplastic cell new therapeutic target novel novel anticancer drug outcome forecast overexpression premature protein complex public health relevance research study three dimensional cell culture tumor growth tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Aneuploidy and chromosomal instability (CIN) are remarkably common in solid tumors including breast cancers. Identifying and characterizing recurring genetic and epigenetic changes in aneuploid cancers will have tremendous impact on cancer prevention, diagnosis and treatment. TRIP13 was ranked as one of the top genes associated with CIN (#12 in the CIN70 signature), and its overexpression was also observed in breast cancers with poor prognosis in multiple microarray studies. However, the working mechanism of TRIP13 and the pathological significance of TRIP13 overexpression in breast cancer development remain unclear. Our preliminary work found that TRIP13, a member of the AAA-ATPases, is a novel kinetochore protein and directly interacts with mitotic checkpoint silencing protein p31comet. TRIP13 knockdown delayed metaphase-to- anaphase transition and significantly reduced breast cancer cell proliferation in 2D culture and soft agar plates. The objective of current proposal is to elucidate mitotic functions of TRIP13 and examine the relationship between TRIP13 overexpression and breast cancer development. The central hypothesis is that TRIP13 overexpression promotes untimely mitotic checkpoint silencing, driving CIN and cancer development in mammary epithelial cells. Three specific aims will test the central hypothesis. Aim 1 will assess biochemical functions of TRIP13 in the mitotic checkpoint. Specifically, we will test that TRIP13, through its interaction with p31comet and its ATPase activity disrupts protein complexes required for mitotic checkpoint signaling. In Aim 2, we will use inducible cell lines to modulate TRIP13 expression level and determine the impact on chromosomal stability and cell proliferation in 2D and 3D cell culture models. Aim 3 will examine the effects of TRIP13 overexpression or knockdown on breast cancer cell growth in xenografted mouse models. Together, the proposed work will test potential oncogenic functions of TRIP13 ATPase and assess the possibility to target TRIP13 as a novel means to control breast cancers. The work also addresses some critical knowledge gaps in mitotic checkpoint signaling studies. Dissecting TRIP13 functioning mechanisms represents an important step in our continuous efforts to understand and exploit aneuploidy and CIN in breast cancers.

描述（申请人提供）：非整倍体和染色体不稳定性（CIN）在包括乳腺癌在内的实体肿瘤中非常常见。识别和表征非整倍体癌症的复发性遗传和表观遗传变化将对癌症的预防、诊断和治疗产生巨大影响。TRIP13被列为与CIN相关的顶级基因之一（在CIN70特征中排名第12位），并且在多个微阵列研究中，在预后不良的乳腺癌中也观察到其过表达。然而，TRIP13的作用机制以及TRIP13过表达在乳腺癌发展中的病理意义尚不清楚。我们的初步工作发现，作为aaa - atp酶的成员，TRIP13是一种新的着丝点蛋白，它直接与有丝分裂检查点沉默蛋白p31comet相互作用。在二维培养和软琼脂板中，TRIP13敲低延迟了中期到晚期的转变，并显著降低了乳腺癌细胞的增殖。本研究的目的是阐明TRIP13的有丝分裂功能，并研究TRIP13过表达与乳腺癌发展的关系。核心假设是TRIP13过表达促进了不合时宜的有丝分裂检查点沉默，推动了CIN和乳腺上皮细胞的癌症发展。三个具体目标将检验中心假设。目的1将评估TRIP13在有丝分裂检查点中的生化功能。具体来说，我们将测试TRIP13通过其与p31comet的相互作用及其atp酶活性破坏有丝分裂检查点信号所需的蛋白质复合物。在Aim 2中，我们将使用诱导细胞系来调节TRIP13的表达水平，并在2D和3D细胞培养模型中确定对染色体稳定性和细胞增殖的影响。目的3将在异种移植小鼠模型中检测TRIP13过表达或敲低对乳腺癌细胞生长的影响。总之，拟议的工作将测试TRIP13 atp酶的潜在致癌功能，并评估以TRIP13为目标作为控制乳腺癌的新手段的可能性。这项工作还解决了有丝分裂检查点信号研究中的一些关键知识空白。解剖TRIP13的功能机制是我们不断努力理解和利用乳腺癌非整倍体和CIN的重要一步。